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in sensing and coordinating the body's response to stress.
When mitochondrial in neurons are stressed, mitochondrial unfolded protein response (UPRmt) is induced by releasing the mitochondrial dependent secretion factor "mitokine", And systematically regulate the pressure adaptability and anti-aging ability
of the entire body.
G protein-coupled receptor (GPCR) proteins, as the largest family of membrane protein receptors and drug development targets, play an important role
in transmitting extracellular information into cells and promoting adaptive responses.
However, the question of whether GPCR signaling pathways are involved in mediating mitochondrial stress signaling communication in nerve-peripheral tissues and related physiological functions remains to be answered
.
Cover introduction (officially published on November 7, 2022): The nervous system coordinates systemic metabolism and affects aging
by integrating external and internal signals from the environment and communicating with peripheral tissues.
This image depicts two chemosensory neurons in Caenorhabditis elegans playing an important role
in controlling mitochondrial homeostasis throughout the organism.
This regulation of the nervous stress response makes the body more resistant to stress from a variety of environments
.
Design: Xie RuiOn October 28, 2022, Tian Ye's research group at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences published an online article entitled in the form of a cover long article in the journal Developmental Cell Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C.
elegans.
Research paper
.
The study found that the GPCR-Gαq signaling pathway mediates neuro-gut trans-tissue mitochondrial stress response signaling communication through the release of neuropeptides in a pair of neurons in the head of the nematode, and the article also reveals the regulatory effect
of the GPCR-Gαq signaling pathway on peripheral metabolism, protein homeostasis and immunity.
The research group used C.
elegans to establish a model to study the neuro-gut cross-tissue mitochondrial stress response - the expression of Wnt/EGL-20 ligand protein in the nerve cells of nematodes can induce a response of mitochondrial unfolded protein in the intestine (see BioArt report for details: Cell Tian Ye group reported that Wnt-mediated mitochondrial homeostasis regulation of nerve cells to the intestine - Comments by Cai Shiqing; Experts review NCB | Tian Ye's research group revealed that neuronal stress can be transmitted across generations).
Through genetic screening, a G protein-coupled receptor, srz-75, was identified to be involved in cross-tissue UPRmt signaling
.
The screening also identified a protein disulfide isomerase PDI-6, which mediates the trans-tissue mitochondrial unfolded protein response from nerve to the gut by regulating the stability and secretion of Wnt protein (see BioArt report: Cell Rep | Tian Ye's team revealed the molecular mechanism by which protein disulfide isomerase PDI-6 regulates cross-tissue mitochondrial stress response and lifespan).
The researchers mapped the function of SRZ-75 to a pair of chemosensory neurons ADL
in the head of the nematode by means of fluorescence localization, transgene supplementation, and tissue-specific knockdown.
Using tissue-specific knockout and knockdown techniques, SRZ-75 was found to regulate neuropeptide release through Gαq in the Gα subunit and the downstream Trio Rho guanylate exchange factor signaling pathway, and participated in cross-tissue UPRmt signaling
.
It is worth mentioning that previous studies have found that serotonin, the neurotransmitter involved in cross-tissue UPR mt signaling, is not involved in SRZ-75-Gαq-mediated cross-tissue UPRmt signaling in ADL neurons, indicating that mitochondrial stress in different neurons may regulate mitochondrial homeostasis in peripheral tissues through multiple mechanisms [1-3].
。
To demonstrate that ADL neurons play a key role in neurogut trans-tissue UPR mt signaling, the researchers induced ADL neuronal death through optical and genetic methods, which can attenuate the activation
of cross-tissue UPRmt signaling.
Subsequently, the researchers continuously activated the GPCR/SRZ-75-Gαq signaling pathway in ADL neurons, and found that UPRmt signaling activation in intestinal tissues enhanced the resistance of nematodes to pathogenic bacteria PA14, while alleviating the accumulation of α-synuclein aggregates in muscle tissue that accompanied aging, reducing fat content in intestinal tissue, and causing fragmentation
of mitochondria in epidermis and muscle tissue.
Taken together, this study reveals the molecular mechanism
by which GPCR signaling pathways in a pair of neurons mediate UPRmt signaling across tissues.
This study also further proves the important role of GPCR in regulating the metabolism, protein homeostasis and immunity of the whole body, and provides a theoretical basis
for in-depth understanding of GPCR's regulation of systemic stress response and targeting neurons to promote healthy aging.
(Below)
Figure: Chemosensory neuron ADL coordinates systemic mitochondrial stress responses
through GPCR signaling pathways Tian Ye's research group of the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences has left the postdoctoral student Liu Yangli and doctoral student Zhou Jun as the co-first authors of the paper, and the doctoral student Zhang Ning, associate researcher Wu Xueying, postdoctoral Zhang Qian, doctoral student Zhang Wenfeng and graduated doctoral student Li Xinyu are also involved in the work
.
Original link: https://doi.
org/10.
1016/j.
devcel.
2022.
10.
001
Pattern maker: Eleven
References
1 Durieux, J.
, Wolff, S.
& Dillin, A.
The cell-non-autonomous nature of electron transport chain-mediated longevity.
Cell 144, 79-91, doi:10.
1016/j.
cell.
2010.
12.
016 (2011).
2 Berendzen, K.
M.
et al.
Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis.
Cell 166, 1553-1563, doi:10.
1016/j.
cell.
2016.
08.
042 (2016).
3 Zhang, Q.
et al.
The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.
Cell 174, 870-883 e817, doi:10.
1016/j.
cell.
2018.
06.
029 (2018).
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.
